Dietary zinc may ultimately become complexed with any of an estimated 200 different zinc-binding proteins. Until recently, the site or sites where zinc deficiency alters cellular function and compromises the regulation of appetite has not been known. In our label we have made several novel findings that allow us to present hypotheses regarding the integrity of the appetite-regulating functions of the hypothalamus. We believe that reduced zinc status alters the cellular physiology of appetite-regulating neuropeptides, causing the loss of appetite we refer to as zinc deficiency- induced anorexia. We believe that zinc deficiency is a cause or accelerating factor in anorexia nervosa and other loss of appetite syndromes. Our broad hypotheses are: (1) Reduced zinc status suppresses the synthesis and/or processing of appetite-stimulating neuropeptide Y (NPY), reducing the normal drive for food intake mediated by NPY. (2) Alterations in levels of growth hormone releasing hormone (GRF) are observed when zinc deficient rats are repleted with normal levels of zinc and regain normal appetite. Our preliminary data supports these hypotheses are: Neuropeptide Y gene expression is reduced significantly in zinc deficient rats Zinc deficient rats consume reduced amounts of only carbohydrate when allowed to self-select from macronutrient diets; carbohydrate intake is known to be driven by NPY Injections of NPY into the hypothalamus of a zinc deficient rat will restore food intake to normal levels Zinc-deficient rats that are repleted with zinc are characterized by a surge in specific protein intake that correlates with a transient increase in GRF levels The normal diurnal food preference cycle (for rats) of carbohydrate preference early in the dark cycle and increased preference for protein and fat later in the dark phase is disrupted by zinc deficiency. Our research plan will utilize molecular-based methods to characterize the integrity of the hypothalamus as a function of zinc status. This includes measurements of gene expression, peptide levels, processing of peptides, and receptor studies. ln-vivo infusion and withdrawal of brain chemicals will be performed utilizing brain cannulation methodology. The proposed experiments address a critical, unexplored area between appetite-regulation and zinc status. The project utilizes an array of molecular-based methods to investigate an unexplained problem in nutritional science recognized for over 30 years, zinc deficiency-induced anorexia. A strength of this proposal includes the interdisciplinary team of collaborators assembled with extremely wide.ranging areas of expertise. The proposed studies are needed to understand and treat appetite-related disorders.